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PubMed2001

A nonlabeled method to evaluate cortisol production rate by modeling plasma CBG-free cortisol disposition.

This study aimed to develop a nonlabeled method for the measurement of cortisol production rate to evaluate adrenal function. The cortisol production rate determination requires that of cortisol clearance, which is not a parameter but a variable resulting from the saturable binding of cortisol to corticosteroid-binding globulin (CBG). Our method is based on evaluation of the plasma clearance of the CBG-free cortisol fraction. This parameter was evaluated from a pharmacokinetic model of total plasma cortisol disposition that takes into account specific binding of the corticoid to CBG in the plasma. We have shown that the CBG-free cortisol kinetics and CBG-binding parameters thus evaluated are not statistically different from those obtained by the radioisotopic method and equilibrium dialysis, suggesting that the plasma CBG-free cortisol clearance is independent of the total plasma cortisol concentrations and represents the actual parameter of cortisol elimination. We validated this modeling approach by using it to calculate the in vivo entry rate of cortisol mimicked by the perfusion of cortisol at a known rate.

Animals↗
PubMed2002

Differential regulation of adrenal corticosteroids after restriction-induced drinking in rats.

Water-restricted rats exhibit a rapid decrease in plasma corticosterone after drinking. The present study examined the effect of restriction-induced drinking on plasma aldosterone and plasma clearance of corticosterone. Rats were water restricted for 6-7 days and then killed before or 15 min after water administration; plasma and adrenal hormones were assayed. Plasma and adrenal corticosterone decreased after drinking without a change in plasma corticosteroid-binding globulin; plasma ACTH decreased or did not change. In contrast, plasma aldosterone did not change or increased after drinking; plasma renin activity was elevated by water restriction and increased further after drinking. In another experiment, rats were adrenalectomized, and corticosterone and aldosterone were replaced with pellets and osmotic minipumps, respectively. Rats were water restricted and killed. There was a small decrease in plasma corticosterone but no change in aldosterone after drinking in adrenalectomized animals. These data suggest that changes in plasma steroids after restriction-induced drinking result from zone-specific responses of the adrenal to known secretagogues, with minimal contribution from increased plasma clearance.

Adrenal Glands↗
PubMed2003

Differential mechanisms for regulation of the stress response across latitudinal gradients.

We examined plasticity of the stress response among three populations of the white-crowned sparrow (Zonotrichia leucophrys). These populations breed at different elevations and latitudes and thus have breeding seasons that differ markedly in length. We hypothesize that in populations where birds raise only one or rarely two broods in a season, the fitness costs of abandoning a nest are substantially larger than in closely related populations that raise up to three broods per season. Thus individuals with short breeding seasons should be less responsive to stressors and therefore less likely to abandon their young. In our study, baseline and handling-induced corticosterone levels were similar among populations, but corticosteroid-binding globulins differed, leading to a direct relationship between stress-induced free corticosteroid levels and length of breeding season. There were also population-specific differences in intracellular low-affinity (glucocorticoid-like) receptors in both liver and brain tissue. Although investigations of population-based differences in glucocorticoid secretion are common, this is the first study to demonstrate population-level differences in binding globulins. These differences could lead to dramatically different physiological and behavioral responses to stress.

Adrenal Cortex↗
PubMed1997

Evidence that brief stress may induce the acute phase response in rats.

Exposing rats to a single session of inescapable tail shock (IS) reduces corticosteroid binding globulin (CBG) 24 h later (Fleshner et al., Endocrinology 136: 5336-5342, 1995). The present experiments examined whether reductions in CBG are differentially affected by controllable vs. identical uncontrollable tail shock, are mediated by IS-induced glucocorticoid elevation, or reflect IS-induced activation of the acute phase response and whether IS produces fever. The results demonstrate that 1) equivalent reductions in CBG are observed in response to escapable tail shock or yoked IS, 2) IS-induced CBG reduction is not blocked by adrenalectomy in rats that receive basal corticosteroid replacement or by pretreatment with RU-38486, and 3) IS appears to activate the acute phase response, since IS reduces serum levels of an acute-phase negative reactant (CBG), increases serum levels of acute-phase positive reactants (haptoglobin and alpha 1-acid glycoprotein), and increases core body temperature 20-24 h later.

Adrenalectomy↗
PubMed2000

Treadmill running produces both positive and negative physiological adaptations in Sprague-Dawley rats.

Exercise training produces a vast array of physiological adaptations, ranging from changes in metabolism to muscle mitochondrial biogenesis. Researchers studying the physiological effects of exercise often use animal models that employ forced exercise regimens that include aversive motivation, which could activate the stress response. This study examined the effect of forced treadmill running (8 wk) on several physiological systems that are sensitive to training and stress. Forced treadmill running produced both positive and negative physiological adaptations. Indicative of positive training adaptations, exercised male Sprague-Dawley rats had a decrease in body weight gain and an increase in muscle citrate synthase activity compared with sedentary controls. In contrast, treadmill running also resulted in the potentially negative adaptations of adrenal hypertrophy, thymic involution, decreased serum corticosteroid binding globulin, elevated lymphocyte nitrite concentrations, suppressed lymphocyte proliferation, and suppressed antigen-specific IgM. Such alterations in neuroendocrine tissues and immune responses are commonly associated with chronic stress. Thus treadmill running produces both positive training adaptations and potentially negative adaptations that are indicative of chronic stress. Researchers employing forced activity need to be aware that this type of exercise procedure also produces physiological adaptations indicative of chronic stress and that these changes could potentially impact other measures of interest.

Adaptation, Physiological↗
PubMed1984

Extravascular CBG-like sites in rat kidney and mineralocorticoid receptor specificity.

To determine the intrarenal distribution of extravascular corticosteroid-binding globulin- (CBG) like sites, we measured the specific binding of [3H]corticosterone to supernatants prepared from papilla-inner medulla, outer medulla, and cortex from adrenalectomized rats. Renal papilla-inner medulla of exhaustively perfused kidneys contained 8-20 times higher concentrations of such sites than cortex or outer medulla. The ontogeny and steroid specificities of such sites were identical to those of plasma CBG; their molar concentration in the inner medulla-papilla was 4 times that of plasma CBG, consistent with local accumulation of CBG. Cytosols from all three zones bound [3H]aldosterone in the presence of RU-26988, a highly specific synthetic glucocorticoid, with high affinity (Kd 4 degrees C, 0.3-0.4 X 10(-9) M) and limited capacity (papilla-inner medulla, 23-34; outer medulla, 15-16; cortex, 12-17 fmol/mg). In papilla-inner medulla the apparent specificity of such [3H]aldosterone binding sites was aldosterone greater than corticosterone greater than dexamethasone, in contrast to aldosterone = corticosterone greater than dexamethasone in outer medulla and cortex. We propose that extravascular CBG confers mineralocorticoid specificity on the papilla-inner medulla [3H]aldosterone binding sites. In addition, given the higher levels of extravascular than intravascular CBG and the recurrent vascular architecture of the renal medulla-papilla, a countercurrent exchange model is proposed for renewable sequestration of corticosterone in the region.

Aldosterone↗
PubMed1999

Evidence for the synthesis of corticosteroid-binding globulin in human placenta.

We demonstrated the expression of corticosteroid-binding globulin (CBG) in human placenta using reverse transcription-polymerase chain reaction-Southern blot analysis and immunohistochemical and immunoblotting studies. In the RT-PCR-Southern blot analysis, only one predicted PCR product was detected without nonspecific products in all samples of human placenta and 3A (tPA-30-1) human placental cells. In Western blot analysis, polyclonal anti-CBG antibodies recognized a protein of approximately 55 kD in the protein extracts prepared from 3A (tPA-30-1) cells. Additionally, CBG mRNA expression was demonstrated by in situ hybridization in the syncytiotrophoblasts. Immunohistochemical studies performed on the placenta demonstrated the presence of specific immunoreactivity in the syncytiotrophoblast layer surrounding the chorionic villi. These findings suggest that CBG is synthesized in human placenta during pregnancy in addition to its synthesis in the liver.

Adult↗
PubMedDate not supplied

Levels of corticosteroid-binding globulin mRNA in human ovarian cancers.

To understand the role of corticosteroid-binding globulin (CBG) in the intracellular steroidal actions in human ovarian cancers, the level of CBG mRNA expression was evaluated in normal ovarian tissues and in ovarian cancers using competitive reverse transcription-polymerase chain reaction-Southern blot analysis. The expression of CBG mRNA was detected in all normal ovaries and ovarian cancers analyzed. There were no significant differences in the mean CBG mRNA levels between normal ovaries and ovarian cancers. The expression in normal ovaries was significantly higher (p < 0.01) in the premenopause than in the postmenopause. A high expression of CBG mRNA was observed in 11 out of 29 cases (38%) of ovarian cancer in comparison with normal ovaries. There was no difference in the expression among the histological classifications or clinical stages of ovarian cancers. These data suggest that human normal ovaries and ovarian cancers might synthesize CBG intracellularly, ovarian cancers might conserve a progesterone-associated property via CBG, and the regulation of intracelluar CBG expression might be changed in some cancers.

Adult↗
PubMed2002

Perinatal maternal food restriction induces alterations in hypothalamo-pituitary-adrenal axis activity and in plasma corticosterone-binding globulin capacity of weaning rat pups.

We investigated the effects of perinatal maternal malnutrition on the hypothalamo-pituitary-adrenal (HPA) axis activity in both basal and stressful conditions in newborn rats at weaning. Mothers from the control group were fed ad libitum. Mothers exposed to food restriction received 50% (FR50) of the daily intake of pregnant dams during the last week of gestation (Pre group), lactation (Post group) or both periods (PP group) in order to compare the long-term effects of gestational and/or lactational restriction. FR50 reduced the body growth of pups from the Post and PP groups as soon as day 11 until day 21 after birth. At weaning, pups of the Post and PP groups showed reduced adrenal, thymus and liver weights. Although the plasma adrenocorticotropic hormone (ACTH) level was reduced in pups, FR50 affected neither corticotropin-releasing hormone expression and peptide synthesis in the hypothalamus nor proopiomelanocortin expression in the adenohypophysis. Basal circulating levels of corticosterone were not markedly affected by FR50, but free corticosterone concentration was increased in the PP group. Plasma corticosterone-binding globulin (CBG) was decreased in newborns from both the Post and PP groups. Mineralocorticoid receptor gene expression was significantly increased in both CA1 and CA3 hippocampal areas in the PP group. Glucocorticoid receptor gene expression was increased in CA1, CA2 and dentate gyrus hippocampal areas in the Pre group, as well as in CA1, CA3 and DG areas in the Post group. The ether inhalation-induced plasma ACTH increase was weaker in pups from the Post and PP groups. Similarly, the ether inhalation-induced plasma corticosterone increase returned to basal levels in the Post group, or to weaker values than baseline in the PP group 90 min after this stressful procedure. The present work suggests that maternal food restriction during the perinatal period (gestation and lactation) or during lactation only reduces the postnatal somatic growth of pups and disturbs the activity of the HPA axis at weaning under both resting and stress conditions. A reduction in the plasma CBG-binding capacity, associated with a probable increase in hippocampal corticosteroid receptors, could reinforce glucocorticoid-mediated negative feedback and shorten stress-induced activation of the HPA axis in pups at weaning.

Adrenal Glands↗
PubMed2002

Ovarian ultrasound and ovarian and adrenal hormones before and after treatment for hyperthyroidism.

OBJECTIVE: To relate thyroid, steroid and pituitary hormones to ovarian ultrasonographic findings in hyperthyroid patients before and during treatment. STUDY DESIGN: Ultrasonography of the ovaries and serum hormone determination by immunoassay were performed before and during thiamazole therapy in 18 women of fertile age treated for hyperthyroidism at the Danderyd Hospital from 1996 to 1998. RESULTS: When hyperthyreotic, the patients had elevated serum levels of sex hormone-binding globulin (SHBG) and subnormal values of cortisol, free testosterone (fT) and dehydroepiandrosterone (DHEA). In the euthyreotic state following treatment, endocrine variables were normalized. Patients with a short duration of the disease had higher pretreatment levels of free thyroxine (fT4), SHBG and testosterone and lower corticosteroid binding globulin (CBG) and cortisol levels compared to patients with a long duration of the disease. The pretreatment ultrasonographic picture was abnormal in 16 of 18 patients. Of the 8 patients who were examined by ultrasonography after 3 months of treatment, all but 1 showed a normal picture. Samples from patients showing an abnormal ultrasonographic picture had significantly higher fT4 and lower free testosterone (fT) values than samples from patients with a normal ultrasonographic picture. CONCLUSION: Ultrasonographic findings showing a multicystic/multifollicular picture, resembling polycystic ovaries (PCO), in hyperthyroidism may be related to direct effects of thyroid hormones on the ovaries and/or altered intraovarian androgen environment due to elevated SHBG levels. It is highly recommended to assess the thyroid status in patients with multicystic/multifollicular ovaries/PCO.

Adrenal Cortex Hormones↗
PubMed2002

Altered control of the hypothalamo-pituitary-adrenal axis in adult male rats exposed perinatally to food deprivation and/or dehydration.

Dehydration, a classic homeostatic stressor in rats, leads to a series of well characterized endocrine responses including stimulation of the hypothalamo-pituitary-adrenal (HPA) axis. In this study, the hypothesis to be tested was that a 50% maternal food restriction (FR50) in late gestation and lactation may have long-term repercussions on HPA axis responsiveness to dehydration in offspring. For this purpose, we studied HPA axis activity in 4-month-old control (C) and perinatally malnourished male rats after a 72-hour water deprivation period. Furthermore, we investigated the long-lasting effects of perinatal maternal malnutrition on the basal activity of the HPA axis. Under basal conditions, rats exposed to perinatal malnutrition showed reduced body weight, enhanced mineralocorticoid receptor (MR) mRNA levels in CA2 and CA3 hippocampal areas, but decreased glucocorticoid receptor (GR) mRNA levels in CA1, CA3 and dentate gyrus (DG) areas. In contrast, the levels of corticotropin-releasing hormone (CRH) and vasopressin (VP) mRNAs in the hypothalamic paraventricular nucleus (PVN) as well as of VP mRNA in the supraoptic nucleus (SON) were unaffected by maternal undernutrition. Expression of proopiomelanocortin (POMC) in the adenohypophysis was significantly enhanced, whereas prohormone convertase-1 (PC1) was not affected. Perinatal malnutrition reduced absolute adrenal weight but did not affect circulating levels of adrenocorticotropin (ACTH), corticosterone and free corticosterone as well as corticosteroid-binding globulin (CBG) binding capacity. Seventy-two hours of dehydration induced a decrease in body weight and CRH mRNA levels in PVN of controls as well as of FR50 rats, but also led to a rise in plasma corticosterone and free corticosterone without changing CBG binding capacity. Dehydration also induced an increase in adenopituitary POMC (C) and PC1 (FR50), PVN and SON VP (C) and GR in CA1 hippocampal area (FR50) mRNA levels and plasma ACTH (C), but a decrease in MR in DG (C) and GR in CA3 and DG (C) mRNA levels. We conclude that maternal food restriction during the perinatal period affects (1) the adult basal activity of the HPA axis with mainly opposite effects on hippocampal MR and GR gene expression and an increase in adenopituitary POMC gene expression, and (2) the responsiveness to water deprivation in adults. In the latter case, the rise in plasma ACTH levels, adenopituitary POMC gene expression, hypothalamic VP gene expression, and the decrease in hippocampal MR gene expression in DG and GR gene expression in CA3 and DG observed in controls are lacking in FR50 rats. In contrast, drastic adenopituitary PC1 gene expression occurred in FR50 rats but not in control animals.

Adrenal Glands↗
PubMed1989

Modulation of the neonatal pituitary and adrenocortical responses to stress by thyroid hormones in the rat: effects of hypothyroidism and hyperthyroidism.

Neonatal rats exhibit a period of diminished pituitary and adrenocortical responses to stress during the first 2 weeks of life. Since thyroid hormones are known to affect brain development, modulation of these responses to stress by alterations in thyroid hormone status have been investigated in hypothyroid (Hypo) and hyperthyroid (Hyper) rat pups. Changes in ACTH and corticosterone (B) levels were measured under basal and stress conditions (3 min exposure to ether vapors) in neonates of various ages (day 5-21). Basal T4 and corticosterone-binding globulin (CBG) levels were also measured. Hypo pups were obtained from methimazole-treated mothers and hyperthyroidism was induced by daily subcutaneous injections of L-T4 (100 micrograms/kg BW) from birth on. In Hyper rats, premature onset of ACTH and B responses to stress was observed in 5-day-old rats while significant ACTH and B secretion only appeared by day 10 in vehicle-injected rats. By contrast, ACTH and B responses to stress were delayed in Hypo pups and only occurred by day 21. The lack of ACTH and B responses to stress of 14-day-old Hypo rats could be reversed by one single L-T4 injection (100 micrograms/kg BW) given 24 h, but not 4 h prior to exposure to stress. On day 21, smaller (p less than 0.05) stress-induced ACTH release was observed both in Hypo and Hyper rats compared to intact rats, concomitant with a diminished ACTH secretion following exogenous ovine CRF (10 micrograms/kg BW, i.p.) administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex↗
PubMed1992

Basal ACTH, corticosterone and corticosterone-binding globulin levels over the diurnal cycle, and age-related changes in hippocampal type I and type II corticosteroid receptor binding capacity in young and aged, handled and nonhandled rats.

Basal corticosterone (B) levels increase with age in the rat, a result of decreased negative-feedback inhibition of hypothalamic-pituitary-adrenal (HPA) activity. Postnatal handling increases CNS negative-feedback sensitivity and appears to attenuate some of the changes occurring in the HPA axis in later life. In the experiments described here, we have examined basal HPA function in young (6-8 months) and old (22 months), handled (H) and nonhandled (NH) rats in relation to changes in corticosteroid receptor binding. Among young animals, there were no group differences in basal adrenocorticotropin (ACTH) or B levels at any point in the diurnal cycle. In contrast, plasma ACTH and B levels during the PM phase were significantly higher in old NH animals in comparison to old H animals and to both groups of young animals. The H and NH groups did not differ in in vivo adrenal responsiveness to exogenous ACTH. As expected, ACTH sensitivity was greater in all groups during the PM phase and in general, old animals showed a greater response to ACTH regardless of the treatment group. There were no differences across the groups in AM plasma corticosterone-binding globulin (CBG) levels. However, during the PM phase of the cycle, CBG levels were significantly lower and the percentage of B in the free form was significantly higher in the old NH animals. As expected, levels of free B during the PM phase of the cycle were significantly higher in the old NH animals. Thus, there is a significant increase in the PM corticoid signal in the old NH animals that occurs as a function of elevated B and decreased CBG levels; these age-related changes in basal HPA activity were not seen in the old H animals. Type I (mineralocorticoid-like) receptor binding in the hippocampus did not differ as a function of handling and was significantly reduced with age in both H and NH animals. Type II (glucocorticoid) receptor binding decreased as a function of age in both H and NH animals, but was consistently higher in the H animals. There were no differences in type II receptor binding in the hypothalamus or pituitary as a function of age or handling. These data suggest that the increase in basal HPA activity occurring in aged rats is largely restricted to the dark phase of the cycle and is attenuated by postnatal handling, a treatment that increases hippocampal type II corticosteroid receptor binding.

Adrenocorticotropic Hormone↗
PubMed1997

Decreased hypothalamic-pituitary-adrenal axis sensitivity to cortisol feedback inhibition in human aging.

Aging-related reduction in the sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis to glucocorticoid feedback inhibition has been demonstrated in rodents, but aging effects on glucocorticoid feedback inhibition in humans are unclear. This study assessed the influence of aging on the sensitivity of the human HPA axis to feedback inhibition induced by cortisol. Endogenous cortisol feedback inhibition was removed by treatment with metyrapone, which reduces cortisol synthesis by inhibiting 11 beta-hydroxylase. Feedback inhibition was then reintroduced by infusing exogenous cortisol. Sixteen young (26 +/- 1 years old) and 16 older (70 +/- 2 years old) subjects underwent three study conditions in random order. In the two cortisol infusion conditions, oral metyrapone treatment was followed by intravenous infusion of 0.03 mg/kg/h (83 nmol/kg/h) or 0.06 mg/kg/h (166 nmol/kg/h) cortisol for 150 min. Feedback sensitivity was estimated by the latency to and extent of decline of plasma ACTH concentration during and following the cortisol infusion. In a placebo condition, placebo tablets were substituted for metyrapone and normal saline infusion was substituted for cortisol. Blood samples were drawn twice prior to and at 15-min intervals for 4 h following the onset of the infusions, and plasma was assayed for 11-deoxycortisol, cortisol and ACTH. Plasma cortisol suppression and ACTH and 11-deoxycortisol elevations did not differ between age groups after metyrapone. Older subjects exhibited delayed and blunted ACTH responses to infused cortisol. Within older subjects, the ACTH response to the higher dose cortisol infusion was blunted in older women compared to older men. These data provide direct evidence for reduced responsiveness to glucocorticoid feedback inhibition in human aging.

Adrenal Glands↗
PubMed1997

Central administration of the neurotensin receptor antagonist, SR48692, modulates diurnal and stress-related hypothalamic-pituitary-adrenal activity.

Previous studies in our laboratory suggest that neurotensin (NT) acts centrally to modulate adrenocorticotropin hormone (ACTH) and corticosterone release. In the present studies, we examined hypothalamic-pituitary-adrenal (HPA) function under basal conditions and during restraint stress following central administration of the highly specific NT receptor antagonist, SR48692. Chronic delivery of SR48692 to the paraventricular nucleus (PVN) of the hypothalamus via indwelling central cannulae attenuated both the diurnal- and stress-induced elevations in HPA activity. Thus, SR48692 decreased the diurnal increase in plasma ACTH and corticosterone during the evening phase of the cycle, but did not affect morning levels. Restraint-induced increases in plasma ACTH and corticosterone levels were also significantly reduced in the SR48692-implanted animals. This suggests that the inhibitory effects of SR48692 were restricted to periods of stimulated HPA activity. A decrease in corticotropin-releasing hormone (CRH)-like immunoreactivity was observed within the PVN following chronic SR48692, and parallel decreases in CRH-like immunoreactivity were observed within the external zone of the median eminence. These findings suggest that endogenous NT serves to increase HPA activity during periods of enhanced stimulation.

Animals↗
PubMed1989

Genetic studies of low-abundance human plasma proteins. XII. A new variant of corticosteroid-binding globulin detected by isoelectric focusing/immunoblotting.

Thin-layer polyacrylamide gel isoelectric focusing over the pH range 3.5-5 followed by immunoblotting was used to investigate the occurrence and frequency of genetic variation in corticosteroid-binding globulin (CBG). Plasma samples from US Caucasians (n = 105) and US Blacks (n = 106) from Pittsburgh, Pa., Canadian Indians from Vancouver Island (n = 91) and Nigerian Blacks (n = 116) were analyzed. A complex isoprotein pattern was observed in all individuals tested. Reduction of this pattern to a single primary band following neuraminidase treatment indicates that the observed intraindividual variation is due to variation in the number of sialic acid residues associated with CBG. The CBG variant pattern consisted of a series of isoprotein bands having the same mobility as the common pattern, and a second series of bands at a more acidic isoelectric point. This pattern is consistent with heterozygosity for a rare CBG allele.

Blood Proteins↗
PubMed1979

Interaction of steroid-binding serum proteins with concanavalin A-Sepharose 4B.

The interaction between steroid-finding serum proteins and concanavalin A was studied using affinity chromatography on concanavalin A-Sepharose 4B. The sex hormone-binding globulins of man and rabbit together with the corticosteroid-binding globulins of man, rabbit and guinea pig were all bound quantitatively by the affinity medium. Only two thirds of rat corticosteriod-binding globulin showed an affinity for concanavalin A indicating this protein to be heterogeneous with respect to terminal mannose or glucose residues. The progesterone-binding globulin in pregnant guinea pig serum, possessing the highest carbohydrate content of the proteins investigated, did not bind to concanavalin A-Sepharose 4B. Affinity chromatography on concanavalin A-Sepharose 4B is documented to be a valuable supplement to existing methods for analysing steroid-protein interactions.

Animals↗